Tetrahydrosoquinoline biguanides



TETRAHYDROISQQUINOLINE B IGUANIDES Erich Haack, Heidelberg, and Adolf Hagedorn, Mannheim-Waldhof, Germany, assignors to C. F. Boehringer & Soehne G.m.b.H., Mannheim-Waldhof, Germany No Drawing. Filed Aug. 6, 1959, Ser. No. 831,932

Claims priority, application Germany Aug. 6, 1958 3 Claims. (Cl. 260-288) The present invention relates to new orally effective antidiabetic agents and more particularly to orally efiective biguanide compounds of the tetrahydroisoquinoline series, and to a process of making the same.

It is known that certain biguanide compounds have antidiabetic properties (see, for instance, Archiv f. exp. Pathol. PharmacoL, vol. 142 (1929), page 290). However, said compounds are unsuitable in the treatment of diabetes mellitus by oral administration because of their high toxicity. Recently, other biguanide compounds have been found to be orally effective antidiabetic agents (Belgian Patent No. 557,985), but they cause nausea and vomiting in a large number of patients, so that they are also too toxic for administration over a prolonged period of time.

his one object of the present invention to provide new and orally highly eifective antidiabetic biguanide compounds which have a low toxicity combined with a good therapeutical activity.

Another object of the present invention is to provide a simple and efiective process of making such compounds.

Other objects of the present invention and advantageousfeatures thereof will become apparent as the description.

proceeds.

Surprisingly it has been found that heretofore unknown biguanide compounds ofthe tetrahydroisoquinoline series of Formula I wherein R is hydrogen or a lower alkyl radical, are largely free of the disadvantages of heretofore suggested antidiabetic biguanide compounds. Those compounds show a reliable antidiabetic effect in animal tests, even if only small doses are administered. As their toxicity is relatively low, they are of considerable importance for the therapy of diabetes mellitus.

The new biguanide compounds according to the present invention are prepared according to various methods.

For instance, tetrahydroisoquinoline or, respectively, its salts are reacted with dicyandiamide which may be substituted, as indicated by the following equation:

Or, reversing this reaction, a tetrahydroisoquinoline deriv- Patented Sept. 6, 1960- ative of dicyandiamide is reacted with ammonia or an? amine, as indicated by the following equation:

According to another method guanyl tetrahydroisoquinoline may be added to cyanamide which may be substituted, according to the following equation:

Reversing said reaction, Z-cyano tetrahydroisoquinoline may be reacted with guanidine which may be substituted, according to the following equation:

Furthermore, it is possible to prepare thio-substitutecl dicyandiamide derivatives and to subject them to an aminating desulfurization reaction according to the following equation:

The following examples serve to illustrate the present. invention without, however, limiting the same thereto.

Example 1 34 g. of tetrahydroisoquinoline hydrochloride are inti-- mately mixed with 16.8 g. of dicyandiamide. The mixtureis heated in an oil bath of a temperature of 142 C. for 55 minutes. The resulting reaction product is boiled with. cc. of ethanol. After cooling, the solution is filtered; by suction. 34.8 g. of the biguanide compound of Formula II are obtained. Melting point: 226-228 C.

i E N-CNH-ONH1.HO1

II I 1,1- (benzo- [3.4] -pentamethy1en) -biguanid-hydrochlorid hydroisoquinoline are refluxed with 120 cc. of 3 N hydrochloric acid for 3 /2 hours. The reaction mixture is then evaporated in; a vacuum and the residue is recrystallized from ethanol. 21 g. of the biguanide compound of Formula 'III are obtained. Melting point: 196198 C.

NH NH N- "1NH("JNH-GH;.H01

III 1,1-(benzo-[3.4]-pentamethylen)-5-methyl-biguanidhydrochlorid I11 place, of tetrahydroisoquinoline and its hydrochloride. used in therpreceding examples, there may be employed equim'olecularamounts of other acid addition salts of tetrahydroisoquinoline, such as the phosphate, sulfate, nitrate, and others.

In place of dicyandiamide and methyl dicyandiamide used in the preceding examples, the reaction according to the present invention may be carried out with other alkyl substituted dicyandiamides such as the ethyl, npropyl, isopropyl, n-butyl, isoamyl dicyandiamide and the like. Otherwise the procedure is the same as described in said examples.

The new tetrahydroisoquinoline biguanide compounds accordingto the present invention are administered in solid form, preferably in shaped form, such as in the form of tablets, pills, dragees, lozenges, and the like shaped preparations, or in powder form, preferably enclosed in gelatin and the like capsules. Administration in liquid form, such as in the form of emulsion, suspensions, sirups, cough drops, and the like is also possible. These solid and liquid preparations are produced in a manner known to the art of compounding and processing pharmaceutical products, whereby the conventional diluting agents, binding agents, lubricants, expanding agents, and the like may be employed.

The new compounds are preferably administered in the form of their acid addition salts such as the hydrochloride, sulfate, phosphate, nitrate, or the like. Salts with organic acids may also be used such as the salts with acetic acid, citric acid and succinic acid.

Of course many changes and variations in the reactants,

the processes used in preparing the new ten'ahydroisoquinoline compounds, the reaction conditions, temperature, and duration, the solvents employed, the methods of working up the reaction products and of purifying the same, and the like may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

We claim:

1. The tetrahydroisoquinoline biguanide compound of the formula 2. The tetrahydroisoquinoline biguanide compound of the formula NE NH and its pharmaceutically acceptable acid addition salts',

andthe tetrahydroisoquinoline biguanide compounds of the formula wherein Ris a lower alkyl radical and their pharmaceu tically acceptable acid addition salts.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No, 2351 843 September 6 1960 Erich Haack et a1.

certified that error appears in the above numbered pat- It is hereby the said Letters Patent should read as ent requiring correction and that corrected below.

Column 1, lines 60 to 65, the upper right hand portion of the equation should appear as shown below instead of as 1n the Signed and sealed this 18th day of July I961o (SEAL) Attest:

ERNEST W. SWIDER Attesting Officer DAVID L. LADD Commissioner of Patents 

3. THE TETRAHYDROISOQUNIOLINE BIGUANIDE COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE TETRAHYDROISOQUINOLINE BIGUANIDE COMPOUND OF THE FORMULA 